NIMENRIX

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Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Nimenrix is located below.

Recent activity for Nimenrix

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle. At this time, no PAAT is available for Nimenrix. When the PAAT for Nimenrix becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Nimenrix

Date SBD Issued: 2013/05/13

The following information relates to the original authorization of the new drug submission for Nimenrix.

Meningococcal polysaccharide groups A, C, W-135 and Y conjugate vaccine
Solution, intramuscular
Drug Identification Number (DIN): 02402904
GlaxoSmithKline Inc.
New Drug Submission Control Number: 154290

On March 5, 2013, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the vaccine Nimenrix.

The market authorization was based on quality, (chemistry and manufacturing) non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Nimenrix is favourable for the active immunization of individuals from 12 months to 55 years of age against invasive meningococcal diseases caused by Neisseria meningitidis serogroups A, C, W-135, and Y.

1. What was approved?
2. Why was Nimenrix approved?
3. What steps led to the approval of Nimenrix?
4. What follow-up measures will the company take?
5. What post-authorization activity has taken place for Nimenrix?
6. What other information is available about drugs?
7. What was the scientific rationale for Health Canada's decision?

1. What was approved?

Nimenrix, an active immunizing agent, was authorized for the active immunization of individuals from 12 months to 55 years of age against invasive meningococcal diseases caused by Neisseria (N.) meningitidis serogroups A, C, W-135, and Y.

Nimenrix is contraindicated for subjects with known hypersensitivies to any component of the vaccine. Nimenrix was approved for use under the conditions stated in the Nimenrix Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

The safety and immunogenicity of Nimenrix in children under 12 months of age and in adults over 55 years of age have not been established.

Nimenrix will only confer protection against N. meningitidis serogroups A, C, W-135, and Y. The vaccine will not protect against other N. meningitidis subgroups.

Nimenrix is presented as a powder and diluent for solution and injection. Nimenrix contains several medicinal ingredients:

• N. meningitidis serogroup A polysaccharide (5 µg)
• N. meningitidis serogroup C polysaccharide (5 µg)
• N. meningitidis serogroup W-135 polysaccharide (5 µg)
• N. meningitidis serogroup Y polysaccharide (5 µg)
• Each polysaccharide is conjugated to tetanus toxoid carrier protein (total of approximately 44 µg).

In addition to the medicinal ingredients, the powder contains sucrose and trometamol, and the diluent contains sodium chloride and water for injection.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Nimenrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

2. Why was Nimenrix approved?

Health Canada considers that the benefit/risk profile of Nimenrix is favourable for the active immunization of individuals from 12 months to 55 years of age against invasive meningococcal diseases caused by Neisseria meningitidis serogroups A, C, W-135, and Y.

Invasive meningococcal disease is an acute and serious illness caused by the bacterium Neisseria (N.) meningitidis. Invasive disease may lead to meningitis, in which the bacteria infect the fluids and membranes (called meninges) covering the brain and the spinal column, or septicemia. In Canada, five of the N. meningitidis serogroups (A, B, C, W-135, and Y) are responsible for the majority of disease.

The immunogenicity of one dose of Nimenrix has been evaluated in four pivotal studies involving over 4,000 participants from 12 months to 55 years of age. Vaccine efficacy was inferred from the demonstration of immunologic non-inferiority to comparator meningococcal vaccines. Immunogenicity was measured by using rabbit complement serum bactericidal assay (rSBA) or human complement serum bactericidal assay (hSBA) which are biomarkers for protective efficacy against meningococcal serogroups A, C, W-135, and Y.

The clinical data submitted included data from four pivotal studies as well as data from supportive studies that demonstrated the immunogenicity and safety of Nimenrix for the proposed indication. By conjugating capsular polysaccharides to a protein carrier that contains T-cell epitopes, meningococcal conjugate vaccines like Nimenrix change the nature of the immune response to capsular polysaccharides from T-cell independent to T-cell dependent. The T-cell dependent response elicited by conjugate vaccines can occur in children less than 2 years of age and results in a strong anamnestic (memory) response to a booster dose of the vaccine.

The immunogenicity and safety of Nimenrix were assessed when Nimenrix was administered concomitantly with other common vaccines, including: Fluarix (seasonal influenza vaccine); Twinrix (hepatitis A and hepatitis B vaccine); Synflorix (10-valent pneumococcal conjugate vaccine); and Priorix Tetra (measles, mumps, rubella, and varicella vaccine). Nimenrix can also be given concomitantly with combined diphtheria-tetanus-acellular pertussis vaccines in the second year of life, including combination DTPa vaccines with hepatitis B, inactivated polio or Haemophilus influenzae Type b, such as Infanrix hexa (combined DTPa, Hepatitis B, Poliovirus and Haemophilus influenzae Type b vaccine).

The safety evaluation for Nimenrix was based on 8,108 subjects who have been vaccinated with one dose of Nimenrix in clinical studies including data for 2,237 toddlers (12 months to 23 months), 1,809 children (2 to 10 years), 2,011 adolescents (11 to 17 years) and 2,051 adults (>18 years).

Administration of Nimenrix was shown to be generally well-tolerated. No safety signals were identified in the clinical development of Nimenrix. All serious adverse events (SAEs) were considered not related to vaccination and resolved without sequelae, with exception of five SAEs reported in three subjects vaccinated with Nimenrix which were considered as causally related to vaccination. These five events were as follows: abdominal pain and gastritis, concussion and syncope, floppy infant, blighted ovum, and convulsion. One SAE reported during the conduct of clinical studies was that of death [that is (i.e.) drowning]. This event was not considered related to vaccination.

The most common adverse events with Nimenrix (>10%) are pain and redness at the site of injection, headache, fever, loss of appetite, swelling, irritability, drowsiness and fatigue. For a full list of all adverse events (AEs) reported with Nimenrix, see the Product Monograph. Nimenrix must not be used in people who are hypersensitive (allergic) to the active substances or any of the other ingredients.

The safety and immunogenicity of Nimenrix when administered during pregnancy or lactation and in patients with immunodeficiency have not been evaluated. This is indicated in the Warnings and Precautions section of the approve Product Monograph for Nimenrix.

A Risk Management Plan (RMP) for Nimenrix was submitted by GlaxoSmithKline Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product. Due to limited information regarding vaccine effectiveness, post-market surveillance will be particularly important. The need for a Risk Minimization Plan will be re-evaluated by GlaxoSmithKline Inc. should a safety signal be detected from any of the ongoing clinical studies as well as from the planned post-authorization pharmacovigilance activities described in this RMP.

Overall, the benefits of Nimenrix outweigh the risks for active immunization of individuals from 12 months to 55 years of age against invasive meningococcal diseases caused by N. meningitidis serogroups A, C, W-135, and Y. Nimenrix has an acceptable safety profile based on the submitted non-clinical data and clinical studies. The identified safety issues can be managed through labelling and pharmacovigilance. Appropriate warnings and precautions are in place in the Nimenrix Product Monograph and address the general safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the  Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3. What steps led to the approval of Nimenrix?

Submission Milestones: Nimenrix

Submission Milestone	Date
Pre-submission meeting:	2009/08/13
Submission filed:	2012/03/21
Screening
Screening Acceptance Letter issued:	2012/05/18
Review
On-Site Evaluation:	2012/11/26
Quality Evaluation complete:	2013/03/04
Clinical Evaluation complete:	2013/02/21
Labelling Review complete:	2013/03/04
Notice of Compliance issued by Director General, Therapeutic Products Directorate:	2013/03/05

The Canadian regulatory decision on the quality, non-clinical and clinical review of Nimenrix was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4. What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the  Food and Drugs Act and  Regulations.

Due to limited information regarding vaccine effectiveness, post-market surveillance will be particularly important. The need for a Risk Minimization Plan will be re-evaluated by GlaxoSmithKline Inc. should a safety signal be detected from any of the ongoing clinical studies as well as from the planned post-authorization pharmacovigilance activities described in this RMP.

5. What post-authorization activity has taken place for Nimenrix?

Summary Basis of Decisions (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

At this time, no PAAT is available for Nimenrix. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6. What other information is available about drugs?

Up to date information on drug products can be found at the following links:

• See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
• See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
• See the Drug Product Database (DPD) for the most recent Nimenrix Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
• See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
• See the Patent Register for patents associated with medicinal ingredients, if applicable.
• See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the  Food and Drug Regulations, if applicable.

7. What was the scientific rationale for Health Canada's decision?

Clinical Basis for Decision

Clinical Pharmacology

Invasive meningococcal disease is an acute and serious illness caused by the bacterium Neisseria (N.) meningitidis. Invasive disease may lead to meningitis, in which the bacteria infect the fluids and membranes (called meninges) covering the brain and the spinal column, or septicemia. In Canada, five of the N. meningitidis (A, B, C, W-135, and Y) are responsible for the majority of disease.

Anti-capsular meningococcal antibodies protect against meningococcal diseases via complement-mediated bactericidal killing. Nimenrix induces the production of bactericidal antibodies against capsular polysaccharides of serogroups A, C, W-135 and Y when measured by assays using either rabbit complement serum bactericidal assay (rSBA) or human complement serum bactericidal assay (hSBA). By conjugating capsular polysaccharide to a protein carrier that contains T-cell epitopes, meningococcal conjugate vaccines like Nimenrix change the nature of immune response to capsular polysaccharide from T-cell independent to T-cell dependent.

The pharmacodynamics of Nimenrix were assessed through the analysis of immunogenicity described in the Clinical Efficacy section. Pharmacokinetic studies are not directly applicable to vaccines.

For further details, please refer to the Nimenrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Invasive disease caused by the N. meningitidis serogroups A, C, W-135 and Y occurs at relatively low rates as endemic disease and in unpredictable and short-lived outbreaks of epidemic illness thus making pre-authorization efficacy trials unfeasible. The World Health Organization's (WHO) position paper (Meningococcal vaccines, November 2011) indicated that "Due to the relatively low incidence of meningococcal disease, pre-authorization clinical efficacy studies may not be feasible. Meningococcal polysaccharide and protein conjugate vaccines are authorized based on evidence of an immune response in vaccinated subjects using serum bactericidal activity (SBA) as the immunologic correlate of protection". Therefore, meningococcal conjugate vaccines have been authorized based on immunological correlates of protection.

The efficacy of Nimenrix was inferred from the demonstration of immunologic non-inferiority to authorized meningococcal vaccines. Immunogenicity was measured by using rSBA or hSBA which are biomarkers for protective efficacy against meningococcal serogroups A, C, W-135 and Y.

Pivotal Studies

Four pivotal studies provided evidence of immunogenicity in support of the authorization of Nimenrix. All four studies were open, randomized, and active-controlled primary vaccination studies designed to demonstrate in four different age groups the non-inferiorities and safety of Nimenrix as compared to the comparator vaccines below:

1. Study 039: Nimenrix versus (vs.) Meningitec in toddlers (12-23 months of age).
2. Study 081: Nimenrix vs. Menjugate in children (2-10 years of age).
3. Study 071: Nimenrix vs. Menactra in adolescents and adults (10-25 years of age).
4. Study 035: Nimenrix vs. Mencevax-ACWY in adults (18-55 years of age).

Study 039 - Toddlers (12-23 months of age)

The co-primary objectives of Study 039 for immunogenicity were:

• to demonstrate the non-inferiority of Nimenrix conjugate vaccine as compared to Meningitec (a conjugate vaccine for N. meningitidis serogroup C), in terms of serogroup C serum bactericidal antibodies (rSBA-MenC);and
• to demonstrate the immunogenicity of Nimenrix for the N. meningitides serogroups A, W-135, and Y, in terms of bactericidal antibodies to N. meningitides serogroups A, W-135, and Y.

The criterion for non-inferiority for serogroup C was that the lower limit of the two-sided standardized asymptotic 95% confidence interval (CI) for the group difference in the percentages of subjects with rSBA-MenC titre ≥1:8 was greater than or equal to the pre-defined limit of  -10%. The criterion for immunogenicity for serogroups A, W-135, and Y was that the lower limit of the two-sided exact 95% CI for the Nimenrix group proportion of subjects with rSBA titre ≥1:8 was greater than or equal to the pre-defined limit of 90%. Both non-inferiority objectives were met.

Study 081 - Children (2-10 years of age)

The primary objective of Study 081 was to demonstrate non-inferiority of Nimenrix compared to the conjugate vaccine Menjugate in terms of serum bactericidal antibody vaccine response to N. meningitidis serogroup C.

The non-inferiority of Nimenrix compared to Menjugate in terms of serum bactericidal antibody vaccine response to rSBA-MenC, one month after vaccination was demonstrated as the lower limit of the 95% CIs on the difference between Nimenrix and the Menjugate group was -5.25%, which was above the pre-specified non-inferiority limit of -10%. Note: Nimenrix met the criterion for non-inferiority for serogroup C only, as Menjugate is a meningococcal serogroup C conjugate vaccine.

Study 081 demonstrated the non-inferiority of Nimenrix when compared to Menjugate for rSBA-MenC titres and significantly higher rSBA antibody responses were induced against serogroups A, W-135 and Y.

Study 071 - Adolescents and Adults (10-25 years of age)

The primary objective of Study 071 was to demonstrate the non-inferiority of Nimenrix when compared to Menactra (vaccine for N. meningitidis serogroups A, C, W-135, and Y)in terms of the percentage of subjects with serum bactericidal activity (using human complement) against N.meningitidis serogroup A (hSBA-MenA), hSBA-MenC, hSBA-MenW-135, and hSBA-MenY with respect to vaccine response one month after vaccination. Vaccine response was defined as an hSBA titre of ≥1:8 in subjects initially seronegative (hSBA titre <1:4) and as a 4-fold increase in titre in subjects initially seropositive (hSBA titre >1:4).

For each serogroup, the criterion for non-inferiority was that the lower limit of the two-sided 95% CI for the percentage of subjects with hSBA vaccine response one month after vaccination (Nimenrix - Menactra) was greater than or equal to the pre-defined clinical limit of -10%.

Nimenrix was demonstrated to be immunologically non-inferior to Menactra in terms of the percentage of subjects with hSBA-MenA, hSBA-MenC, hSBA-Men-W-135, and hSBA-MenY vaccine response one month after vaccination (all the lower limits of the two-sided 95% CI for the difference between groups were ≥-10%).

Study 035 - Adults (18-55 years of age)

Study 035 had multiple primary objectives including the demonstration of non-inferiority of the bactericidal antibody (rSBA) vaccine response induced by Nimenrix (from the 3 manufactured lots pooled) compared to Mencevax (vaccine for N. meningitidis serogroups A, C, W-135, and Y).

Nimenrix met the criteria for non-inferiority when compared to Mencevax-ACWY in terms of the percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY vaccine response one month after the vaccination (all the lower limits of the two-sided 95% CI for the difference between groups were ≤10%).

Supportive Studies

Co-administration with Other Vaccines

Additional data from the pivotal studies as well as further supportive studies supported the use of Nimenrix when administered concomitantly with other common vaccines, including: Fluarix (seasonal influenza vaccine); Twinrix (hepatitis A and hepatitis B vaccine); Synflorix (10-valent pneumococcal conjugate vaccine); and Priorix Tetra (measles, mumps, rubella, and varicella vaccine). Nimenrix can also be given concomitantly with combined diphtheria-tetanus-acellular pertussis vaccines in the second year of life, including combination DTPa vaccines with hepatitis B, inactivated polio or Haemophilus influenza Type b, such as Infanrix hexa (combined DTPa, Hepatitis B, Poliovirus and Haemophilus Influenzae Type b vaccine).

The immunogenicity and safety of Nimenrix was evaluated when sequentially administered or co-administered with Infanrix hexa (DTPa-HBV-IPV/Hib vaccine) in the second year of life. The administration of Nimenrix one month after Infanrix hexa resulted in lower MenA, MenC and MenW-135 rSBA geometric meant titres (GMTs). The clinical relevance of this observation is unknown, as ≥99.4% of subjects (n = 178) had rSBA titres ≥8 for each group (A, C, W-135, Y).

The non-inferiority of Nimenrix co-administered (co-ad) with Infanrix hexa compared to Nimenrix administered alone was demonstrated: the lower limit of the two-sided standardized asymptotic 95% CI for the group difference (Co-ad minus Nimenrix) in the percentages of subjects with rSBA titre ≥8 was above the pre-defined clinical limit of -10% for the four serogroups.

The non-inferiority of Infanrix hexa co-administered with Nimenrix compared to Infanrix hexa alone in terms of GMCs of antibodies to pertussis toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) was demonstrated as the lower limit of the two-sided 95% CI on the adjusted GMC ratios for anti-PT, anti-FHA and anti-PRN were above the pre-defined limit of 0.67. The non-inferiority of the co-administration was also demonstrated in terms of percentages of subjects with antibody concentrations to anti-PRP antibody concentration for Haemophilus influenza type b vaccine ≥1.0 mg/mL and to hepatitis B surface antigen (HBsAg) ≥10 mIU/mL the lower limit of the two-sided 95% CI around the difference between groups (Co-ad minus Infanrix hexa) was above the pre-specified limit of -10%.

As the data suggest that the immune response to Nimenrix may be lowered when it is administered one month after Infanrix hexa, recommendations have been included in the Product Monograph for Nimenrix suggesting that whenever possible, Nimenrix and a tetanus toxoid (TT) containing vaccine, such as a DTPa-HBV-IPV/Hib vaccine, should be co-administered or Nimenrix should be administered at least one month before the TT-containing vaccine.

The Product Monograph for Nimenrix also states that one month after co-administration with Synflorix (a 10-valent pneumococcal conjugate vaccine), lower Geometric Mean antibody Concentrations (GMCs) and opsonophagocytic assay (OPA) antibody GMTs were observed for one pneumococcal serotype (18C conjugated to tetanus toxoid carrier protein). The clinical relevance of this observation is unknown. This finding is not unexpected when many vaccine antigens are co-administrated. There was no impact on the co-administration of the other nine pneumococcal serotypes.

Persistence and Immune Memory Studies

In Study 059, the persistence of the immune response was evaluated by hSBA after vaccination with Nimenrix compared to vaccination with Menactra in adolescents and adults 11-25 years of age primed in Study 052.

At one year following the primary vaccination 76% of the subjects were included in the evaluation. The percentage of subjects 11-25 years of age with hSBA antibody titres ≥1:8 in serogroups MenC, MenW-135, and MenY ranged from 94.9% to 98.5% for those subjects that received Nimenrix. In comparison, subjects that received Menactra had MenC, MenW-135, and MenY hSBA titres ≥1:8 that ranged from 73.3%-86.7%. In the MenA serogroup, the percentage of subjects with hSBA antibody titres ≥1:8 was 29.1% in the Nimenrix group and 31.3% in the Menactra group.

For all four serotypes (A, C, W, Y), the persistence of the antibodies elicited by Nimenrix and Menactra was comparable.

Study 021, subjects previously vaccinated with a plain meningococcal polysaccharide vaccine were immunized with Nimenrix, and an increase in rSBA GMTs were observed for all four serogroups in these individuals.

Ongoing Studies

Ongoing extension studies will monitor persistence of the immune response.

In addition, ongoing Study 085 is currently underway to evaluate the immunogenicity of Nimenrix in adults >55 years of age.

The immunogenicity and safety of a booster dose 4 years after vaccination of Nimenrix will be evaluated in study 039 follow up period.

Special Populations

It may be expected that in patients receiving immunosuppressive treatment or patients with immunodeficiency, an adequate immune response may not be elicited.

Immunogenicity has not been assessed in patients with increased susceptibility to meningococcal infection due to conditions such as terminal complement deficiencies and anatomic or functional asplenia. In these individuals, an adequate immune response may not be elicited.

The immunogenicity in patients under the age of 12 months and over the age of 55 years has not been established.

For more information, refer to the Nimenrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety evaluation for Nimenrix was based on a pooled analysis of 8,108 subjects who had been vaccinated with one dose of Nimenrix in clinical studies. The pooled analysis included data from 2,237 toddlers (12 months to 23 months), 1,809 children (2 to 10 years), 2,011 adolescents (11 to 17 years), and 2,051 adults (>18 years).

Pivotal Studies

The pivotal clinical studies are described in the Clinical Efficacy section.

Study 039 - Toddlers (12-23 months)

In Study 039, healthy toddlers 12 through 23 months of age were administered either:

• 1 dose of Nimenrix.
• 1 dose of Nimenrix co-administered with a first dose of Priorix-Tetra (measles, mumps, rubella, and varicella vaccine).
• 1 dose of Priorix-Tetra.
• 1 dose of Meningitec (a conjugate vaccine for N. Meningitidis serogroup C).

The safety data of Nimenrix was comparable with Meningitec in toddlers 12 to 23 months, except for local reactions: redness >30 mm (4.4% - Nimenrix vs. 0.8% - Meningitec); and swelling >30 mm (4.1% - Nimenrix vs. 0.8% - Meningtec).

Irritability was the most frequently reported solicited general symptom in the 4 groups (50.7% in the Nimenrix + Priorix-Tetra group; 43.5% in the Meningitec group; 40.9% in the Nimenrix group; and 38.7% in the Priorix-Tetra group).

Study 081 - Children (2-10 years)

In Study 081, healthy children 2 to 10 years of age were administered 1 dose of Nimenrix or 1 dose of Menjugate (a conjugate vaccine for N. Meningitidis serogroup C).

2 to 5 years

In subjects 2 to 5 years of age, the reactogenicity profile of Nimenrix was comparable with Menjugate. During the 4-day post-vaccination period, redness was the most frequently reported solicited local symptom in each group (35.2% - Nimenrix and 39.6% - Menjugate).

Irritability was the most frequently reported solicited general symptom in each group (15.4% - Nimenrix and 11.3% - Menjugate). Drowsiness was also reported (14.2% - Nimenrix and 11.3% - Menjugate). Fever ≥37.5°C was reported by 5.6% of the subjects in the Nimenrix group and 5.7% of the subjects in the Menjugate group. The majority of fevers were measured by the rectal route (66.7% - Nimenrix group and 100% - Menjugate).

6 to 10 years

In subjects 6 to 10 years of age, the reactogenicity profile of Nimenrix was comparable with Menjugate with the exception of headache (16.2% - Nimenrix and 4.0% - Menjugate).

During the 4-day post-vaccination period, pain was the most frequently reported solicited local symptom in each group (43.9% - Nimenrix and 54.0% - Menjugate).

Fatigue was the most frequently reported solicited general symptom in each group (22.3% - Nimenrix and 22.0% - Menjugate). Fever ≥37.5°C was reported in 6.8% of the subjects in the Nimenrix group and 2.0% of the subjects in the Menjugate group.

Study 071 - Adolescents and Adults (10-25 years)

In Study071, healthy subjects 10 to 25 years of age were administered 1 dose of Nimenrix or 1 dose of Menactra (ACWY).

The reactogenicity profile of Nimenrix was comparable with Menactra with the exception of Grade 3 pain (2.4% Nimenrix and 0.6% - Menactra).

The most common solicited local symptom during the 4-day post-vaccination period was pain at the injection site, reported by 51.4% and 55.4% of subjects in the Nimenrix and Menactra groups, respectively.

The incidence of redness at the injection site was 25.8% and 20.3% of subjects in the Nimenrix and Menactra groups, respectively. The incidence of swelling was 19.1% in the Nimenrix group and 13.5% in the Menactra group. The majority of these events were Grade 1 in intensity. Grade 3 events of redness (i.e. >50 mm in diameter) were reported by 3 and 6 subjects in the Nimenrix and Menactra groups, respectively. Grade 3 events of swelling (i.e. >50 mm in diameter) were reported by 3 subjects for each of the two vaccine groups.

The most common solicited general symptom was fatigue with an incidence of 27.3% to 29.2% across the two vaccine groups. Headache was reported by 25.5% to 26.4% and gastrointestinal symptoms by 13.1% to 13.5% of subjects across the two vaccine groups.

Study 035 - Adults (18-55 years of age)

In Study035, healthy adults 18 through 55 years of age were administered either:

• 1 dose of Nimenrix;
• 1 dose of Mencevax-ACWY (polysaccharide) vaccine; or
• 1 dose of Nimenrix co-administered with an authorized influenza vaccine, Fluarix.

In subjects 18-55 years of age, the safety data for Nimenrix was comparable with Mencevax-ACWY in terms of Grade 3 general reactions. The reported Grade 3 solicited local reactions in terms of redness & swelling >50mm were 1.3% vs. 0% for Nimenrix and Mencevax ACWY, respectively.

During the 4-day post-vaccination period, pain was the most frequently reported solicited local symptom in each group (21.9% in the Nimenrix + Fluarix group, 19.4% in the Nimenrix group, and 13.5% in the Mencevax-ACWY group). Headache was the most frequently reported solicited general symptom in each group (16.3% - Nimenrix, 14.2% - Mencevax-ACWY, and 13.3% in the Nimenrix + Fluarix group).

Supportive Studies

Co-administration with Other Vaccines

Co-administration with other vaccines, including: Fluarix (unadjuvanted seasonal influenza vaccine); Twinrix (hepatitis A and hepatitis B vaccine); and Priorix Tetra (measles, mumps, rubella, and varicella vaccine) revealed a safety profile similar to that revealed a safety profile similar to that for the vaccines alone or Nimenrix alone.

Overall Analysis of Safety

Administration of the Nimenrix vaccine was shown to be generally well-tolerated and no safety signals were identified in the clinical program. All serious adverse events (SAEs) were considered not related to vaccination and resolved without sequelae, with exception of five SAEs reported in three subjects vaccinated with Nimenrix which were considered as causally related to vaccination. These five events were as follows: abdominal pain and gastritis; concussion and syncope; floppy infant; blighted ovum; and convulsion. No Guillain-Barré Syndrome (GBS) cases were reported during the clinical development of Nimenrix. One SAE reported during the conduct of clinical studies was that of death (i.e. drowning). This event was not considered related to vaccination.

There is limited experience with use of Nimenrix in pregnant women. Animal studies with Nimenrix do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryo/fetal development, parturition or post-natal development; however, Nimenrix should be used during pregnancy only when clearly needed and in cases where the possible advantages outweigh the potential risks for the fetus.

The safety of Nimenrix when administered to breastfeeding women has not been evaluated. It is unknown whether Nimenrix is excreted in human breast milk; therefore, Nimenrix should only be used during breast-feeding when the possible advantages outweigh the potential risks.

Appropriate warnings and precautions are in place in the approved Nimenrix Product Monograph to address the general safety concerns.

Although Nimenrix contains tetanus toxoid, this vaccine does not substitute for tetanus immunization.

A more rapid waning of serum bactericidal antibody titres against MenA than for other serogroups (C, W-135, Y) has been observed when using human complement in the assay. In individuals expected to be at particular risk of exposure to MenA and who received a first dose of Nimenrix more than one year earlier, consideration may be given to administering a second dose of Nimenrix. Available data indicate that a second dose will elicit an anamnestic (memory) immune response to all four meningococcal types in the vaccine. Currently there is very limited information available on the safety of a second dose of Nimenrix.

For more information, refer to the Nimenrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

A Risk Management Plan (RMP) for Nimenrix was submitted by GlaxoSmithKline Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product. Due to limited information regarding vaccine effectiveness, post-market surveillance will be particularly important. The need for a Risk Minimization Plan will be re-evaluated by GlaxoSmithKline Inc. should a safety signal be detected from any of the ongoing clinical studies as well as from the planned post-authorization pharmacovigilance activities described in this RMP.

Non-Clinical Basis for Decision

The results of the non-clinical studies as well as the potential risks to humans have been included in the Nimenrix Product Monograph.

• Pharmacodynamics study: it confirmed that vaccine containing conjugated polysaccharides is more immunogenic than a free-polysaccharide formulation and induced high level of polysaccharide specific antibodies.
• Toxicity studies: the vaccine formulations used in the toxicology studies were well tolerated based on local tolerance, acute toxicity, repeated dose toxicity, developmental/reproductive toxicity and fertility studies.

In view of the intended use of Nimenrix, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Nimenrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

Quality Basis for Decision

Nimenrix (meningococcal polysaccharide groups A, C, W-135 and Y conjugate vaccine) is a tetravalent meningococcal polysaccharide conjugated vaccine consisting of four drug substances: purified polysaccharides of N. meningitidis serogroups A, C, W-135 and Y (5 µg of each) conjugated to tetanus toxoid (total of approximately 44 µg) as a carrier protein. It is a non-adsorbed, freeze-dried preparation presented as monodose vials to be reconstituted with a diluent (saline solution). The vaccine does not contain any preservatives or adjuvants.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that all four drug substances consistently exhibit the desired physicochemical structure and biological activity.

Results from process validation studies indicate the methods used during processing are sufficient to control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within acceptable limits.

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process development were adequately described. In-process and release results, stability, and characterization data have also been provided and support the comparability assessment.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

The manufacturing of the four drug substances consists of the production of five process intermediates (MenA polysaccharide, MenC polysaccharide, MenW-135 polysaccharide, MenY polysaccharide and tetanus toxoid), obtained through fermentation and purification steps. The N. meningitidis serogroups A and C polysaccharides are conjugated indirectly to tetanus toxoid through an adipic dihydrazide (ADH) spacer; the W-135 and Y polysaccharides are conjugated directly to tetanus toxoid to produce the drug substance.

The manufacturing process of each of the five process intermediates and the conjugation procedure for each of the four drug substances were evaluated. The materials used in the manufacturing of the drug substances are considered suitable for their intended use. The manufacturing process is considered to be adequately controlled.

Nimenrix (meningococcal polysaccharide groups A, C, W-135, and Y conjugate vaccine) is supplied as a 0.5 mL dose, consisting of one vial of vaccine and one ampoule or syringe of diluent. The vaccine is provided as a sterile, white, lyophilized powder in a 3-mL single-dose glass vial. In addition, to the active ingredients, the powder contains sucrose and trometamol. The diluent (sodium chloride and water for injection) is a sterile clear and colourless liquid supplied separately in a pre-filled syringe or ampoule. The vials, syringes and ampoules are made of neutral glass Type 1. After reconstitution, Nimenrix is a clear colourless solution for intramuscular injection. The volume per nominal dose is 0.5 mL.

The vaccine is prepared for injection by reconstituting the four component vaccine with the supplied diluent. Each dose (0.5 mL) of reconstituted vaccine contains 5 µg each of meningococcal A, C, W-135, and Y polysaccharide, conjugated to a total of approximately 44 µg of tetanus toxoid carrier protein. Nimenrix does not contain any preservatives or adjuvants.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the  Food and Drug Regulations. The compatibility of the active ingredients with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substances. The specifications provided for each of the four drug substances are considered acceptable. Data from the batch analyses of each of the four drug substances were reviewed and are within the proposed acceptance criteria.

The drug substance packaging is also considered acceptable.

The test specifications and analytical methods used are considered acceptable based on the validation reports submitted for all procedures used for in-process, release, and stability testing for the drug product. The specifications proposed were in line with the characteristics of the vaccine lots tested in clinical studies. Data from the batch analyses of each of the drug product components were reviewed and were within the proposed acceptance criteria.

Health Canada carried out consistency testing of Nimenrix using two different methods to measure total polysaccharide. The results of both methods confirmed consistency of production.

Stability of the Drug Substance and Final Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf-life at 2 to 8°C for Nimenrix is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

The On-Site Evaluation (OSE) was conducted in November 26-30, 2012. Two manufacturing sites were visited. Overall, the operations and facilities were found to be satisfactory; the manufacturing processes were well-controlled confirming the information submitted in the New Drug Submission.

Both sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

No materials of animal origin are used as excipients for the Nimenrix vaccine.